The ontogeny of the human globin genes is an important focus of study both with respect to the fundamental developmental biology and molecular genetics of the control of expression of this complex gene system, but also because modifying this developmental control would be of therapeutic value in the treatment of the prevalent genetic diseases of hemoglobin, such as sickle cell anemia and thalassemia. This has been one of our research emphases for more than 25 years. Among other findings was our demonstration that hydroxyurea, now approved to treat sickle cell anemia by elevating fetal hemoglobin, affects intracellular nitric oxide metabolism, specifically changing cyclic GMP levels. These results brought together our NO (see Annual Reports DK025093 and DK025104) and our sickle cell work and has led us to continue gene expression studies in human hematopoietic cells in collaborative studies. One such study shows that many transcription factors change during ontogeny of human CD34+ erythroid cells in culture, especially related to the JAK-STAT and AKT pathways. In subsequent studies we showed that CD 34+ cells have increased levels of gene expression of the PI3/AKT and MAPK genes related to the mTOR signaling pathways as compared to other hematopoietic cells. We have also used myeloproliferative cells -the main focus of hydroxyurea studies - to show that a variety of angiogenic-related genes are affected by treatment with this agent. More recently these studies have shown that nitric oxide (NO) produced by hydroxyurea, as well as increased synthesis of NO by nitric oxide synthase (NOS) enzymes contribute to the effects of this drug. Our long interest in understanding the pain phenotype in sickle cell patients has resulted in analyses which suggest that there are both central and peripheral nervous system aspects to perception of pain. We have also shown that elevation of Hb F by hydroxyurea decreases sickle cell pain as measured in these studies with external probes. Importantly our data showed that central sensitization to pain is an important component of pain in these patients and is affected by fetal hemoglobin levels. We have also analyzed data from contrast-enhanced ultrasound perfusion imaging of forearm and myocardial blood flow in sickle cell patients and have found that when corrected for degree of anemia hydroxyurea (hydroxycarbamide) increases blood flow in both or organs and muscle blood flow correlates with fetal hemoglobin levels. More recent studies are focused on developing new therapies for sickle cell disease and we have met with representatives of several companies that have potential drugs which alter oxygen affinity and we are having discussions of one or more collaborations with these companies. We have also returned to our previous measurements of NO metabolite levels and of cell-free hemoglobin in these patients, hoping to recruit a larger cohort, to better gauge the potential value of nitrite administration. We are also working with an NIH malaria group to understand the mechanism of cerebral malaria and are evaluating the production and destruction of NO in this condition by measurements of nitrate and nitrite levels in the blood of animal models of cerebral malaria and in red cells from these animals. We continue working with the NIH Office of History in archiving NIH science history, reviewing oral histories, and organizing meetings and lectures, as well as editing symposia on related topics for publication, particularly in the journal Perspectives in Biology and Medicine. We have organized several symposia on the recent history of NIH, one of which was presented in conjunction with the NIH Research Festival. We very recently helped develop an exhibit for NIH on the life and work of C.B. Anfinsen, the former head of this Laboratory (Branch), which was accompanied by a symposium in the fall of 2018 devoted to his career. We have recently completed and submitted a long review of the intracellular polymerization of sickle hemoglobin in the pathogenesis of this disease, with emphasis on historical aspects and written with Drs. Noguchi and Kim-Shapiro, for a new textbook devoted to Sickle Cell Disease.